Is ABCC8 p.Val21Asp (c.62T>A) pathogenic?

ABCC8 p.Val21Asp (c.62T>A) is classified Pathogenic/Likely pathogenic in ABCC8 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-07-04). AlphaMissense: likely pathogenic (0.9106); Very rare (popmax 0.00467%, nfe); Associated with type 2 diabetes mellitus.

What condition is associated with ABCC8 p.Val21Asp (c.62T>A)?

ABCC8 p.Val21Asp (c.62T>A) is associated with type 2 diabetes mellitus, hypoglycemia, leucine-induced, hyperinsulinemic hypoglycemia, familial, 1 (ClinVar).

How common is ABCC8 p.Val21Asp (c.62T>A) in the general population?

ABCC8 p.Val21Asp (c.62T>A) is very rare (popmax 0.00467%, nfe) (gnomAD).

What do computational predictors say about ABCC8 p.Val21Asp (c.62T>A)?

AlphaMissense predicts likely pathogenic (score 0.9106) — an in-silico prediction, not a clinical call.

ABCC8 p.Val21Asp

c.62T>A · rs200670692 · VCV495835

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00467%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type 2 diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.9106	likely pathogenic ✓ concordant with ClinVar
REVEL	0.863	moderately pathogenic-leaning
SaProt	LLR -13.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00467% European (non-Finnish) · 55/1,178,150 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00348% 56/1,609,238 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00467%	21,421
Finnishnot grpmax-eligible	0.00158%	63,214

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCC8
Protein: p.Val21Asp
Coding: c.62T>A
MANE Select: NM_000352
dbSNP: rs200670692
Type: single nucleotide variant
Location: chr11:17476715 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.56 · 8 PDB
Residue 21: a β-strand; a disulfide bond; a UniProt-annotated variant site (in hhf1)

Full ABCC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

type 2 diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypoglycemia, leucine-induced hyperinsulinemic hypoglycemia, familial, 1 diabetes mellitus, transient neonatal, 2 familial hyperinsulinism diabetes mellitus, permanent neonatal 3

Similar variants

ABCC8 p.Val21Ile Uncertain significance ★ ⚠ same residue
ABCC8 p.Val21fs Pathogenic/Likely pathogenic ★★ same residue
ABCC8 p.Val21Phe Likely pathogenic ★ ⚠ same residue
ABCC8 p.Val21= Likely benign ★ same residue
ABCC8 c.1176+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.1333-1013A>G Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.148+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.148+2T>G Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abcc8-p-val21asp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown